Glycogen storage disease type II (GSDII or Pompe disease) is an autosomal recessive metabolic disorder characterized by a deficiency in the lysosomal enzyme acid α-glucosidase (GAA). Patients suffering from the disorder are unable to convert lysosomal stores of glycogen into glucose, which leads initially to accumulation of glycogen in the lysosome, and later to accumulation of glycogen in the cytoplasm and autophagic vesicles of cells. Eventually, the buildup of toxic levels of glycogen damages the cells and impairs proper function. In particular, muscle cell dysfunction is a hallmark of Pompe disease, with symptoms ranging from hypertrophic cardiomyopathy, weakness, skeletal muscle dysfunction and early infant death in infantile onset forms of the disease, to progressive degeneration of skeletal muscle function and respiratory muscle dysfunction in juvenile and adult onset forms of the disease.
Treatment of Pompe disease with enzyme replacement therapy (ERT) has provided partial restoration of muscle function and prolonged survival in some patients. However, prior therapies based on delivery of the 110 kDa precursor GAA protein have achieved delivery of protein only to the lysosome. Delivery of protein exclusively to the lysosome has proven ineffective to clear glycogen build-up in the cytoplasm or other extra-lysosomal spaces. Additionally, approaches based on delivering protein to the lysosome have relied on uptake through mannose-6-phosphate receptors in the lysosome, and high dosages appear to be required.